Therapeutic efficacy of new dimercaptosuccinic acid (DMSA) analogues in acute arsenic trioxide poisoning in mice

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Abstract
The therapeutic efficacy of six newly synthesized analogues of dimercaptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poisoning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso-2,3-di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with protected thiol groups (“prodrugs”), and DMDMS, DEDMS, DnPDMS, and DiPDMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and isopropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 μmol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i.p. or one of the analogues i.p. or via gastric tube (i.g.). Control animals received arsenic trioxide and saline 30 min later. The survival rate was recorded for 30 days. All of the animals treated with DMSA i.p. survived and all controls died within 2 days. Administered i.g., DATSA and DBTSA increased the survival rate to 29% and 43%, and injected i.p. to 86%. Treatment with DMDMS i.p. and i.g., and with DEDMS, DnPDMS, and DiPDMS i.g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To investigate the efficacy of the DMSA analogues in reducing the tissue content of arsenic, male NMRI mice received an s.c. injection of an LD5 of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 μmol/kg body wt). Thirty minutes later, saline (controls) or a single equimolar dose (0.7 mmol/kg) of DMSA i.p., or one of the analogues i.p. or i.g. was administered. The arsenic content of various organs (blood, liver, kidneys, heart, lungs, spleen, small intestine, large intestine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma counter. In all organs investigated, the efficacy of DATSA, DBTSA, DEDMS, and DnPDMS administered i.p and i.g., and of DiPDMS given i.p. in reducing the tissue content of arsenic was significantly higher compared to saline (p<0.05), but not superior to DMSA. Treatment with DMDMS i.p. or i.g., and DiPDMS i.g. showed much less or no reduction. Generally, the elimination rate of arsenic following therapy i.p. was more effective compared to i.g. treatment. It is concluded that DATSA and DBTSA, i.p. and i.g., and DEDMS, DnPDMS, and DiPDMS, given i.p., are effective arsenic antidotes, but are not superior to DMSA. Different substitution of the DMSA molecule resulted in altered therapeutic efficacy. The dependence of the antidotal efficacy on the route of administration (i.p., i.g.) indicates differences in absorption or metabolism of the analogues. Shielding of the thiol groups did not exhibit any advantage, high lipophilicity of an arsenic antidote might be unfavourable, and the limitation to the extracellular space might be the key to higher antidotal success in acute arsenic trioxide poisoning.